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Integrative epigenomic and genomic analysis of malignant pheochromocytoma

Sandgren, Johanna (author)
Uppsala universitet,Institutionen för kirurgiska vetenskaper,Institutionen för genetik och patologi
Andersson, Robin (author)
Uppsala universitet,Centrum för bioinformatik
Rada-Iglesias, Alvaro (author)
Uppsala universitet,Centrum för bioinformatik
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Enroth, Stefan (author)
Uppsala universitet,Centrum för bioinformatik
Åkerström, Göran (author)
Uppsala universitet,Endokrinkirurgi
Dumanski, Jan P. (author)
Uppsala universitet,Institutionen för genetik och patologi
Komorowski, Jan (author)
Uppsala universitet,Centrum för bioinformatik
Westin, Gunnar (author)
Uppsala universitet,Endokrinkirurgi
Wadelius, Claes (author)
Uppsala universitet,Institutionen för genetik och patologi
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 (creator_code:org_t)
Springer Science and Business Media LLC, 2010
2010
English.
In: Experimental and Molecular Medicine. - : Springer Science and Business Media LLC. - 1226-3613 .- 2092-6413. ; 42:7, s. 484-502
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Epigenomic and genomic changes affect gene expression and contribute to tumor development. The histone modifications trimethylated histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) are epigenetic regulators associated to active and silenced genes, respectively and alterations of these modifications have been observed in cancer. Furthermore, genomic aberrations such as DNA copy number changes are common events in tumors. Pheochromocytoma is a rare endocrine tumor of the adrenal gland that mostly occurs sporadic with unknown epigenetic/genetic cause. The majority of cases are benign. Here we aimed to combine the genome-wide profiling of H3K4me3 and H3K27me3, obtained by the ChIP-chip methodology, and DNA copy number data with global gene expression examination in a malignant pheochromocytoma sample. The integrated analysis of the tumor expression levels, in relation to normal adrenal medulla, indicated that either histone modifications or chromosomal alterations, or both, have great impact on the expression of a substantial fraction of the genes in the investigated sample. Candidate tumor suppressor genes identified with decreased expression, a H3K27me3 mark and/or in regions of deletion were for instance TGIF1, DSC3, TNFRSF10B, RASSF2, HOXA9, PTPRE and CDH11. More genes were found with increased expression, a H3K4me3 mark, and/or in regions of gain. Potential oncogenes detected among those were GNAS, INSM1, DOK5, ETV1, RET, NTRK1, IGF2, and the H3K27 trimethylase gene EZH2. Our approach to associate histone methylations and DNA copy number changes to gene expression revealed apparent impact on global gene transcription, and enabled the identification of candidate tumor genes for further exploration.

Keyword

histone code
DNA copy number changes
gene expression
oncogenes
pheochromocytoma
tumor suppressor genes
MEDICINE
MEDICIN

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